A-kinase anchoring protein BIG3 coordinates oestrogen signalling in breast cancer cells

Tetsuro Yoshimaru, Masaya Ono, Yoshimi Bando, Yi-An Chen, Kenji Mizuguchi, Hiroshi Shima, Masato Komatsu, Issei Imoto, Keisuke Izumi, Junko Honda, Yasuo Miyoshi, Mitsunori Sasa and Toyomasa Katagiri ()
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Tetsuro Yoshimaru: Institute for Genome Research, Tokushima University
Masaya Ono: National Cancer Center Research Institute
Yoshimi Bando: Tokushima University Hospital
Yi-An Chen: National Institutes of Biomedical Innovation, Health and Nutrition
Kenji Mizuguchi: National Institutes of Biomedical Innovation, Health and Nutrition
Hiroshi Shima: Miyagi Cancer Center Research Institute
Masato Komatsu: Institute for Genome Research, Tokushima University
Issei Imoto: Institute of Biomedical Sciences, Tokushima University Graduate School
Keisuke Izumi: Graduate School of Medicine, Tokushima University Graduate School
Junko Honda: National Hospital Organization Higashitokushima Medical Center
Yasuo Miyoshi: Hyogo College of Medicine
Mitsunori Sasa: Tokushima Breast Care Clinic
Toyomasa Katagiri: Institute for Genome Research, Tokushima University

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract Approximately 70% of breast cancer cells express oestrogen receptor alpha (ERα). Previous studies have shown that the Brefeldin A-inhibited guanine nucleotide-exchange protein 3–prohibitin 2 (BIG3-PHB2) complex has a crucial role in these cells. However, it remains unclear how BIG3 regulates the suppressive activity of PHB2. Here we demonstrate that BIG3 functions as an A-kinase anchoring protein that binds protein kinase A (PKA) and the α isoform of the catalytic subunit of protein phosphatase 1 (PP1Cα), thereby dephosphorylating and inactivating PHB2. E2-induced PKA-mediated phosphorylation of BIG3-S305 and -S1208 serves to enhance PP1Cα activity, resulting in E2/ERα signalling activation via PHB2 inactivation due to PHB2-S39 dephosphorylation. Furthermore, an analysis of independent cohorts of ERα-positive breast cancers patients reveal that both BIG3 overexpression and PHB2-S39 dephosphorylation are strongly associated with poor prognosis. This is the first demonstration of the mechanism of E2/ERα signalling activation via the BIG3–PKA–PP1Cα tri-complex in breast cancer cells.

Date: 2017
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DOI: 10.1038/ncomms15427

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